Alternatives to animal tests have emerged over the last decades mainly as cell cultures aiming to replace on by one an animal experiment, producing similar (correlating)results.To some extent, in silico modeling, mainly as structure activity relationships, has added to this repertoire.In fact, about 50 methods have been internationally validated and are used to some extent replacing, reducing or refining (3Rs) animal use.However, these were typically tests for topical and acute effects of substances, while the progress to substitute for long-term and systemic effect testing was quite limited.They use cells similar to the traditional animal experiments as black boxes, where the outcome of a substance exposure is recorded.More recently only, we have started to discuss the shortcomings of both the animal tests and our cell culture work in more detail.This might actually serve as a door opener for new approaches making evident the limitations of animal tests in an objective not only animal welfare driven way.At the same time, awareness of the shortcomings of our in vitro work helps to improve them and increases the credibility and reliability of research results.